The telomerase enzyme has been proposed to represent the key element that allows non-immortalized cells to become immortalized. According to a prevailing model, in the absence of telomerase, normal cells have only a limited replicative potential as manifested by their entrance into senescence and crisis upon extended passage. Telomerase is usually repressed in most normal cell lineages and its sudden expression during crisis appears to allow cells unlimited proliferative ability - the phenotype of immortalization. This trait enables malignant cell clones to expand to a size where they become clinically detectable and ultimately life threatening. hTERT, the gene specifying the catalytic subunit of telomerase, has recently been cloned. Many of the proposed experiments will examine the mechanisms by which the hTERT gene becomes depressed when cells pass through crisis and become immortalized. These experiments will focus on the transcription factors that interact with the hTERT promoter, including those specified by the myc and E6 oncoproteins, and the mechanisms that affect hTERT expression. Yet other work will assess whether whether ectopic expression of hTERT enables normal human cells to avoid senescence and crisis, immortalizes them and, in cooperation with known oncogenes, leads to their malignant transformation.